One of the body’s most vital functions is to convert metabolic products and toxins into soluble, safe substances which can then be eliminated via the urine or via the gall bladder into the intestines. The liver plays an all-important role in this process, which is known as detoxification or biotransformation.

Recent research has shown that many patients with chronic fatigue syndrome or ME have a disordered liver biotransformation ability. We simply don’t know what other diseases and health disorders may be promoted by a toxic overload resulting from such dysfunction, but progress is beginning to be made in looking at specific detoxification pathways and relating underfunctioning of these to the development of diseases like Parkinsonism, motor neurone disease (also known as ALS) and Alzheimer’s disease.

A number of biochemical pathways are involved in liver biotransformation. These are normally grouped into oxidation, reduction or hydrolysis reactions (Phase I) and conjugation reactions (Phase II).

Phase I detoxification

Phase I reactions, which are catalysed by a group of liver microsomal enzymes known as cytochrome P450 oxidases, introduce oxygen into the structure of toxins or metabolites. Typically the toxins are converted to alcohols and aldehydes by this process, then into acids, which are water-soluble and can be excreted via the urine.

The intermediate substances created during Phase I detoxification, which include reactive oxygen species (free radicals), can be extremely toxic – far more so than the original toxins. Their harmful effects are primarily controlled by antioxidant nutrients and enzymes, therefore a plentiful supply of these substances is essential. Apart from free radicals, other intermediate metabolites include epoxides, chloral hydrate (which is identical to the knock-out drug often known as the ‘Mickey Finn’) and endogenous benzodiazepines – substances similar to Valium and other tranquillizers and sleeping pills. This makes it easier to understand how chronic fatigue can develop when a toxic overload is present.

The more P450 enzymes have to be induced, the more toxic intermediates will be present in the human body. These enzymes are induced by caffeine, alcohol, dioxin and other pollutants, exhaust fumes, high protein diets, oranges and tangerines, organophosphorus pesticides, paint fumes, steroid hormones, and a variety of drugs including paracetamol (acetaminophen), diazepam tranquillizers and sleeping pills, the contraceptive pill and cortisone. Substances which can inhibit P450 enzymes include carbon tetrachloride, carbon monoxide, barbiturates, quercetin and naringenin (found in grapefruit). The oxidation reaction can also be blocked by an excess of toxic chemicals, a lack of enzymes, lack of nutrients and/or loss of oxygen. Such blocking results in a build-up of more toxic substances such as formaldehyde and other aldehydes in the target tissue. This can in turn lead to a spreading phenomenon, with increasing sensitivity to more chemicals such as ketones and alcohols, and eventually even to natural chemicals occurring in foods, pollen and mould. A build-up of aldehydes can in severe cases lead to tissue crosslinking, causing vasculitis with possible seizures and brain damage.

Intestinal overgrowth with Candida albicans, as well as the peroxidation of polyunsaturated fats, are known sources of aldehydes. The fatigue, foggy thinking and ‘brain fag’ linked with candidiasis may be due to an overloading of the detoxification system with aldehydes, which can even lead to a reverse reaction of aldehyde to alcohol. Extreme intolerance to alcohol consumption may occur in these individuals, as it does in those diagnosed with ME or chronic fatigue syndrome.

Although most aldehydes in the body are thought to occur as intermediate metabolites, external sources include exposure to formaldehyde gas (which is given off by new carpets, curtains and other furnishings) and breakdown products of ethylene glycol and methanol.

Cytochrome P450 and other oxidizing enzymes also oxidize amines such as phenylethylamine found in chocolate, tyramine found in cheese, and catecholamines (adrenaline, noradrenaline and dopamine). These are oxidized into aldehydes by mitochondrial monoamine oxidase (MAO). If this enzyme is blocked, for instance by MAO inhibitor drugs used to treat depression, tyramine, for instance, cannot be metabolized and hypertension can develop as a chemical sensitivity reaction.

Phase II detoxification (conjugation)

There are five main conjugation categories, including acetylation, acylation (peptide conjugation with amino acids), sulphur conjugations, methylations and conjugation with glucuronic acid. Some substances enter Phase II detoxification directly, others come via Phase I pathways. Conjugation involves the combining of a metabolite or toxin with another substance which adds a polar hydrophilic molecule to it, converting lipophilic substances to water-soluble forms for excretion and elimination. Individual xenobiotics and metabolites usually follow a specific path, so whereas caffeine is metabolized by P450 enzymes, aspirin-based medications are conjugated with glycine, and paracetamol (acetaminophen) with sulphate.

Acetylation

Acetylation requires pantothenic acid to function. It is the chief degradation pathway for compounds containing aromatic amines such as histamine, serotonin, PABA, P-amino salicylic acid, aniline and procaine amide. It is also a pathway for sulphur amides, aliphatic amines and complex hydrazines.

A proportion of the general population – perhaps up to 50 per cent – are slow acetylators. This rises to as high a level as 80 per cent among the chemically sensitive population. Their N-acetyltransferase activity is thought to be reduced, and this prolongs the action of drugs and other toxic chemicals, thus enhancing their toxicity.

Acylation

Acylation uses acyl CO-A with the amino acids glycine, glutamine and taurine. Conjugation of bile acids in the liver with glycine or taurine is essential for the efficient removal of these potentially toxic compounds. Disturbed acylation by pollutant overload decreases proper levels of bile in the gastrointestinal tract, resulting in poor assimilation of lipids and fat-soluble vitamins, and disturbed cholesterol metabolism.

Toluene, the most popular industrial organic solvent, is converted by the liver into benzoate, which, like aspirin and other salicylates, must then be detoxified by conjugation with the amino acid glycine (glycination). Large doses of glycine and N-glycylglycine are used in treating aspirin overdose. Benzoate is present in many food substances and is widely used as a food preservative.

Glycine is a commonly available amino acid, but the capacity to synthesize taurine may be limited by low activity of the enzyme cysteine-sulfinic acid decarboxylase. Damage can occur to this enzyme directly by pollutants, or by overload/over-use resulting in depletion.

Both taurine- and glycine-dependent reactions require an alkaline pH: 7.8 to 8.0. Environmental medicine specialists may alkalinize over-acidic patients by administering sodium and potassium bicarbonate in order to facilitate these reactions.

Glutathione conjugation, using the amino acid glutathione in its reduced form, is used for the transformation of xenobiotics such as aromatic disulphides, naphthalene, anthracene, phenanthacin compounds, aliphatic disulphides and the regeneration of endogenous thiols from disulphides. There is a cycle of replenishment for glutathione, allowing it to be reformed after conversion to glutathione reductase. Heavy metals can inhibit this cycle, thus preventing replenishment.

Sulphate conjugation (sulphation)

Neurotransmitters, steroid hormones, certain drugs and many xenobiotic and phenolic compounds such as oestrone, aliphatic alcohols, aryl amines and alicyclic hydroxysteroids employ sulphation as their primary route of detoxification. Steventon at Birmingham University (UK) has found that many sufferers from parkinsonism, motor neurone disease and Alzheimer’s disease as well as environmental illness, tend to have a reduced ability to produce sulphate from the amino acid cysteine in their body, and instead accumulate cysteine. Sulphate may be ingested from food, but is also produced by the action of the enzyme cysteine dioxygenase on cysteine. This process is known as sulphoxidation. The body’s ability to conjugate toxins with sulphate is ‘rate limited’ by the amount of sulphate present; if there is inadequate sulphate, toxins and metabolites can accumulate, perhaps building up to levels which cause degeneration of nervous tissue after several decades. Steventon’s findings are a matter for serious concern. How many individuals are given the opportunity to find out whether they are poor sulphoxidizers and to reduce their chances of developing the above mentioned diseases by improving their sulphoxidation ability?

Large doses of N-acetyl-cysteine (NAC) are a standard treatment for paracetamol (acetaminophen) overdose.

Methylation

According to environmental medicine specialist William Rae, the process most often disturbed in the chemically sensitive involves methylation reactions catalysed by S-adenosyl-L-methonine-dependent enzymes. Methionine is the chief methyl donor to detoxify amines, phenols, thiols, noradrenaline, adrenaline, dopamine, melatonin, L-dopa, histamine, serotonin, pyridine, sulphites and hypochlorites into compounds excreted through the lungs. Methionine is needed to detoxify the hypochlorite reaction. The activity of the methyltransferase enzyme is dependent on magnesium, and, due to the frequency of magnesium deficiency, supplementation with this nutrient will often stabilize chemically sensitive patients.

Glucuronidation

Glucuronic acid is a metabolite of glucose. It can conjugate with chemical and bacterial toxins such as alcohols, phenols, enols, carboxylic acid, amines, hydroxyamines, carbamides, sulphonamides and thiols, as well as some normal metabolites in a process known as glucuronidation. For most individuals glucuronidation is a supplementary detoxification pathway. It is a secondary, slower process than sulphation or glycination, but is important if the latter pathways are diminished or saturated. Obese people seem to have an enhanced capacity to detoxify molecules that can use the glucuronidation pathway. However, damage to the capacity for oxidative phosphorylation, which takes place in the mitochondria, is likely to diminish the capacity for glucuronide conjugation.

If the liver’s detoxification pathways are excessively stimulated and overly utilized, they eventually become depleted or begin to respond poorly – being suppressed by toxic chemicals. Once breakdown of the main pathways occurs as a result of pollutant overload, toxins are shunted to lesser pathways, eventually overloading them, and disturbing orderly nutrient metabolism. Chemical sensitivity may then occur, followed by nutrient depletion and finally fixed-name disease.

Interesting facts

Dr William Rae of the Environmental Health Centre in Dallas says that the most severely ill chemically sensitive patients not only have abnormally low antipollutant enzymes in addition to toxic suppression and nutrient depletion, but in some instances antibodies are produced against cytochrome P450 and these may inhibit or decrease its effectiveness.

Environmental medicine specialists have found that almost 35 per cent of chemically sensitive patients are deficient in intracellular sulphur. Not only can this hinder the detoxification of some sulphur-containing and other toxic chemicals, it can enhance the harmful effects of exposure to cyanide from foods such as cassava and almonds as well as from tobacco products. The hereditary disease known as Leber’s optic atrophy involves a genetic defect in the ability to detoxify cyanide, and leads to sudden, permanent blindness on first exposure to cyanide in small amounts such as those ingested from smoking cigarettes.

Many practitioner multimineral supplements in the UK omit iron and copper due to theories that individuals may already be overloaded with these nutrients. However if no overload is present, an unbalanced supplement may promote depletion of the minerals. The Environmental Health Centre in Dallas finds that intravenous infusions to replenish iron stores brings dramatic improvements for the chemically sensitive patient as part of their detoxification process. Copper is also found to help catalyze the cytochrome systems. (NB: self-supplementation with iron and copper should be cautious, to avoid iron and copper overload conditions).

Although the liver microsomal system is the primary site for oxidation of xenobiotics, the cytochrome P450 system is found in other tissues that are exposed to environmental compounds like the skin, lungs, gastrointestinal tract, kidneys, placenta, corpus luteum, lymphocytes, monocytes, pulmonary alveolar macrophages, adrenals, testes and brain, in both the mitochondria and in the nuclear membrane.

Always rinse your washing-up carefully. Pollutants in the form of solvents and detergents can damage and penetrate the cell membrane and damage the contents of the cell.

Vitamin B3 has been shown to accelerate the clearance of aldehydes in some chemically sensitive patients.

Molybdenum, although an essential element, competes with sulphate in its activation step to the important enzyme PAPS and can thus lower sulphate levels and impair sulphation ability. Environmental medicine experts warn that molybdenum supplementation may be contraindicated in individuals with poor sulphation ability.

The substance naringenin, found in grapefruit, can significantly inhibit Phase I detoxification, as can grapefruit itself. This may prove clinically useful in some situations where Phase I activity is too high, (as shown in liver function tests available from nutritional therapists).

Persons who have been exposed to toxic chemicals, drugs and other xenobiotics (foreign substances), have increased requirements for some vitamins. Functional nutritional assays for vitamins B1, B2, B3, B6, B12 and folate, and serum levels of vitamins A, D, C and beta carotene were performed in a random sample of 333 environmentally-sensitive patients prior to treatment. 57.8% were found to be deficient in B6, 37.7% in vitamin D, 34.9% in B2, 32.2% in folate, 27.7% in vitamin C, 21.4% in niacin, 14.9% in B12, 5.6% in vitamin A and 4.6% in beta-carotene. (Ross GH et al: Evidence for vitamin deficiencies in environmentally-sensitive patients. Clinical Ecology 6(2):60-6, 1989.)

Globe artichoke leaf: promotes regeneration of the liver and promotes blood flow in that organ

Silymarin: according to recent research, this herbal extract stabilizes the membranes of liver cells, preventing the entry of virus toxins and other toxic compounds including drugs. Promotes regeneration of the liver.

Turmeric: a cholagogue like dandelion, but may irritate the gastric mucosa. Its advantages are its cheapness and ability to be used in cookery.

These herbs are best taken with strong chamomile tea, which helps to prevent liver spasms caused by gall bladder-stimulating herbs.

The term oestrogen refers not to one hormone but to a group of hormones: oestradiol, oestrone and oestriol, which promote female characteristics and reproductive functions. Oestrogen is made in the ovaries in women, and in the adrenal cortex and peripheral body fat in both men and women. It is also made by the male testes.

During the first half of the menstrual cycle, oestrogen is produced in response to the stimulus provided by follicle stimulating hormone, and renders the female reproductive system ready for fertilization, implantation and nutrition of the early embryo. Female sex drive is not dependent on oestrogen but on male hormones (androgens) synthesized by the female adrenal glands. Poor adrenal function or removal of the adrenals can therefore greatly reduce the sex drive.

Small amounts of testosterone are produced by the ovaries, which then use enzymes to convert them to oestrogen. In the female body an excess of oestrogen (or of progesterone) promotes fluid retention, while an oestrogen deficiency causes hot flushes of menopause.

Pharmaceutical preparations of oestrogen are used in oral contraceptives and as ‘hormone replacement therapy’ (HRT) to relieve menopausal discomforts and treat osteoporosis. Oestrogens in oral contraceptives have an adverse effect on circulation, and have caused venous thrombosis in many Pill users. HRT is associated with dependency problems by suppressing the body’s own natural oestrogen production. Discontinuing the medication can lead to withdrawal symptoms which are identical to the original hot flushes and other problems but more severe. This makes the patient reluctant ever to discontinue the treatment and she may require higher and higher doses to maintain a feeling of well-being. Both oral contraceptives and HRT are associated with a higher risk of some cancers.

Cow’s milk is the most significant source of natural oestrogens in the western diet. However phyto-oestrogens (plant oestrogens also known as isoflavones) are found in many foods, including wheat, rice, soya products, oats, barley, carrots, potatoes, apples, cherries, plums and parsley, and in herbs such as sage leaf, hops and liquorice. Vegetable oils, including safflower, wheatgerm, corn, linseed, peanut, olive, soya and coconut oils, may also be high in phyto-oestrogens. One of the most potent phyto-oestrogens, genistein, is found in soya products. Dietary phyto-oestrogens have been found to have an oestrogen-balancing effect on female health. Both problems of excess oestrogen, such as breast cancer, and problems of inadequate oestrogen, such as hot flushes, are reduced in populations with a high soya intake. Soya products also seem to be effective in preventing cancer of the prostate in men. A large body of scientific research now indicates that phyto-oestrogens are generally protective against cancer and reduce cholesterol levels.

In experimental animals, oestrogen has been shown to influence food intake. On days of the animal’s cycle when oestrogen levels are high there is a decrease in food intake, likewise when animals are given oestrogen-like compounds in their diet.

An excess of oestrogen (in its oestradiol or oestrone rather than oestriol form) can promote tumours of the female reproductive system. In fact these cancers account for half of all cancers in women. Breast cancer is one of the major causes of mortality in the West. Many cases of breast cancer are hormone-dependent; that is to say, removal of the ovaries can, at least temporarily, check their growth. In populations with a high incidence of breast cancer, it has been found that women excrete a larger quantity of total oestrogens in their urine but a smaller quantity of oestriol than women in low-risk populations. The most active form of oestrogen, known as oestradiol, is normally metabolized to oestrone, and then to oestriol. Low oestriol levels suggest that the liver is not performing this metabolizing function adequately. The higher levels of circulating oestradiol may encourage tumour formation. Recent research shows that dietary broccoli may help the liver to metabolize oestrone more efficiently. In a study carried out on 16 men and women, 500 grams of broccoli a day added to their diet resulted in an increase in the cytochrome liver enzymes involved in oestrone metabolism. (Kall MA et al: Effects of dietary broccoli on human in vivo drug metabolizing enzymes: evaluation of caffeine, oestrone and chlorzoxazone metabolism. Carcinogenesis 17(4):793-9, 1996.) High fibre diets can also help to reduce blood oestrone and oestradiol levels (Rose DP et al: High-fibre diet reduces serum estrogen concentrations in premenopausal women. Am J Clin Nutr 54(3):520-5, 1991).

Excess body fat is associated with a higher incidence of female reproductive cancers, and obese women may have elevated oestrogen levels. Because adipose (fat) tissue is a major site of oestrogen synthesis even after the menopause, obese women may have a later menopause with fewer hot flushes and other symptoms.

Oestrogen and antibiotics

Normally over 60 per cent of circulating oestrogen is excreted into the intestines through the bile, to be deconjugated (broken down) by bacterial enzymes. Some of the oestrogen is reabsorbed and excreted in the urine. However, when antibiotics are used, oestrogen reabsorption drops, lower levels are found in the urine, and the quantity found in faeces may be up to 60 times greater than normal. Because of this excessive loss of oestrogen, antibiotics can lead to breakthrough bleeding in women.